Summary Innate immunity is the first line of defense against pathogens and is highly conserved from insects to humans. While many key facets of the innate immune system have been elucidated, there is a fundamental gap in our knowledge of the pathways that restrict arthropod-borne viral infections in the diverse target tissues that are infected during the infection of the mammalian host. Importantly, a molecular understanding of these mechanisms is essential to overcome the lack of effective antiviral therapeutics and combat human disease. The Drosophila immune response is highly homologous to that of vector insects and additionally shares striking similarities with mammalian innate immunity. Using the Drosophila system, we previously found that the emerging bunyavirus Rift Valley Fever virus (RVFV) is sensed by the Drosophila Pattern recognition receptor (PRR), Toll-7, which activates antiviral autophagy and that this is conserved in mammalian cells. We found that TLR2-dependent antiviral autophagy can control RVFV in some cell types while in other cells engagement of TLR2 leads to cell death. Moreover, we found that pharmacological activation of autophagy is restrictive against RVFV in mammalian primary neurons, suggesting that this pathway may be harnessed for antiviral protection. Since tissue-specific signaling of PRR pathways are poorly characterized we screened a panel of PRR agonists for those that could block RVFV infection in neurons and in non-neuronal cells in parallel. We identified two classes of antiviral PAMPs. First, we identified TLR2 agonists as antiviral in both cell types. Since pharmacological activation of autophagy can protect primary mammalian neurons from infection, we suggest that TLR2 activation may be harnessed to defend neurons from encephalitic viruses. Second, we identified Dectin-1 agonists as specifically antiviral in neurons which will be further explored. Therefore, the long-term objective of the proposed research is to understand the molecular mechanisms by which viral infections are sensed and controlled by innate pathways and how this may be harnessed to induce protective defenses in diverse cell types including neurons. To accomplish these goals, this application proposes two specific aims: (1) to identify the mechanism by which RVFV is sensed by TLR2 leading to diverse outcomes, autophagy or cell death; and (2) explore the PRR pathways that can control bunyaviruses in mature mammalian neurons.